The present invention relates to improvements in composition formulation technology, more particularly improvements in the formulation of compressible compositions including one or more active ingredients that are combined with inactive excipients such as binders and/or hardening agents to enable the production of a final compressed form such as a tablet, pellet, bead or the like.
The compressed tablet is one of the oldest and most popular unit forms for oral dosage of medicinal substances. As a result of the introduction of new carriers and compression vehicles, tablets are replacing many forms of pills, powders and capsules. Accordingly, tablets presently represent the largest production volume of all pharmaceuticals and nutritional supplements.
The reasons for the widespread use of tablets are apparent, since tablets facilitate: (1) administration of medication in an accurate dose; (2) fast and accurate dispensing with less chance of error and contamination: (3) ease of administration: (4) administration in a form in which the time and area of contact between the active ingredient and the taste buds are reduced, thus obviating the physiological problems associated with the oral administration of drugs that possess a bitter taste and, in the case of coated tablets, with drugs that possess a disagreeable odor; (5) release of drugs at specific locations in the gastro-intestinal tract to prevent degradation of drugs sensitive to the low pH environment in the stomach, prevent release of drugs that irritate the gastric mucosa in the stomach, and facilitate local action or preferential absorption at specific sites in the tract: (6) enhanced stability by effecting a marked reduction in the surface of the drug exposed to the environment; (7) rapid production; and (8) economy and ease in storage, packaging and shipping.
The preparation of a solid compressed form containing one or more active ingredients (such as drugs or nutrients such as vitamins) requires that the materials to be compressed into the form possess certain physical characteristics that lend themselves to such processing. Among other things, the material to be compressed must be free flowing, must be lubricated, and, importantly, must possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression.
A tablet is formed typically by pressure being applied to the material to be tableted on a tablet press. A tablet press includes a lower punch which fits into a die from the bottom and a upper punch having a corresponding shape and dimension which enters the die cavity from the top after the tableting material fills the die cavity. The tablet is formed by pressure applied on the lower and upper punches. The ability of the material to flow freely into the die is important in order to insure that there is a uniform filling of the die and a continuous movement of the material from the source of the material, e.g. a feeder hopper. The lubricity of the material is crucial in the preparation of the solid dosage forms since the compressed material must be readily ejected from the punch faces.
Since most drugs and nutritional supplements have none or only some of these properties, methods of tablet formulating have been developed to impart these desirable characteristics to the material(s) which is to be compressed into a solid dosage form. Typically, excipients, which impart good flow and compression characteristics to the material as a whole, are added to the active material that is to be compressed. Such properties are typically imparted to these excipients via a pre-processing step such as wet granulation, slugging, spray drying, spheronization, or crystallization. Useful direct compression excipients include processed forms of cellulose, sugars, and dicalcium phosphate dihydrate, among others.
There are three general methods of preparing the materials to be included in the solid dosage form prior to compression: (1) dry granulation; (2) wet granulation; and (3) direct compression.
Dry granulation procedures may be utilized where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted. The method includes mixing the ingredients with a lubricant, if required, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients.
The wet granulation procedure includes mixing the powders to be incorporated into the dosage form and thereafter adding solutions of a binding agent to the mixed powders to obtain a granulation. Thereafter, the damp mass is screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., via tray drying or fluid-bed drying. One disadvantage of the wet granulating technique is that it has been known to reduce the compressibility of some pharmaceutical ingredients including microcrystalline cellulose.
Direct compression is a relatively quick process wherein the powdered materials included in the solid dosage form are compressed directly without modifying their physical nature. Usually, the active ingredient, direct compression vehicle and other ancillary substances, such as a glidant to improve the rate of flow of the tablet granulation and lubricant to prevent adhesion of the tablet material to the surface of the dies and punches of the tablet press, are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets.
Direct compression is usually limited to those situations where the drug or active ingredient has a requisite crystalline structure and the physical characteristics required for formation of an acceptable tablet. However, only a very limited number of substances possess enough cohesive strength and flowability to allow direct compression without previous granulation. A limited number of crystalline materials, such as potassium bromide and potassium chloride, can be compressed without preliminary treatment. Also, drugs such as aspirin and phenolphthalein can be directly compressed after blending with suitable tableting excipients.
It has been estimated that about 20 percent of the materials used for tableting in the pharmaceutical field may be compressed directly. In order to use this method to a greater extent, many more materials are modified either by treating the material in some special way during early stages of preparation, or by adding a direct compression vehicle, i.e., a dry binder or excipient material which will mix with the active ingredient to provide a flowable powder and form an easily compressible carrier.
There are currently several available binders or excipients that can be used as direct compression vehicles. They include spray-dried lactose; anhydrous lactose: microcrystalline cellulose; dicalcium phosphate dihydrate, unmilled; spray-congealed mannitol; ungelatinized starch (e.g., cornstarch), and partially or fully pregelatinized starch.
Microcrystalline cellulose, processed cellulose, has been utilized extensively in the pharmaceutical industry as a direct compression vehicle for solid dosage forms. Microcrystalline cellulose is commercially available under the tradename Emcocel(copyright) from Edward Mendell Co., Inc. and as Avicel(copyright) from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties as long as it is not wet granulated prior to compression.
Many types of partially or fully pregelatinized starches are commercially available for use in direct compression tablet formulations. Pregelatinized cornstarch provides tablets with hardness properties in the range of 1 to 4 Kp. Present demands, however, require hardness levels in the range of 10-14 Kp and higher, an expectation which many starches modified by prior art methods simply can not meet. While the use of starch in tableting formulations is still common practice, problems of uniformity between modified batches and a demand for tablets of greater hardness resulted in its departure from the status of a preferred pharmaceutical excipient.
The prior art also discloses inherently cost ineffective chemically modified starches requiring the additional expense of crosslinking chemicals or functional reagents to produce the desired physical characteristics in the substrate. Disposal problems associated with unwanted reaction by-products further adds to cost and environmental concerns. Also, chemical modification methods yield product in batch quantities, rather than on a continuous or semi-continuous basis and, therefore, are less time efficient. Production rates are further diminished when more than one chemical modification must be made to the starch substrate to yield a product with all of the desired characteristics. Moreover, the starch end product itself often suffers from other limitations similar to the deficient tablet hardness profiles, discussed above. Inferior viscosity, shear resistance and thermal profiles of the starch end product, for example, may frustrate the performance of products incorporating starch modified by prior art means.
Since each excipient added to a formulation necessarily increases the tablet size of the final product, compression techniques are often limited to formulations containing a rather low load of active ingredient per compressed tablet. Solid dosage forms containing the active ingredient to be administered in a relatively high load or dose (e.g., the drug itself comprises a substantial portion of the total compressed tablet weight), could only be directly compressed if the drug itself had sufficient physical characteristics (e.g., cohesiveness) for the ingredients to be directly compressed.
For example, acetaminophen, a widely used analgesic, is considered to be a high load active ingredient. Most commercial compressed tablet formulations include anywhere from 70 to 85% by weight acetaminophen per finished tablet. This high load of active ingredient combined with its rather poor physical characteristics for direct compression has not allowed pharmaceutical manufacturers to use direct compression techniques to prepare the final tablets.
Thus, another limitation of direct compression as a method of tablet manufacturing is the potential size of the compressed tablet. If the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active with other excipients to attain an acceptably sized tablet with the desired amount of active ingredient, such as acetaminophen. Usually the amount of filler/binder or excipients needed in wet granulation is less than that required for direct compression since the process of wet granulation contributes to some extent toward the desired physical properties of a tablet. Even so, other reasons, such as for example the loss of compressibility associated with the wet granulation of MCC, prevent wet granulation from always being the solution to increase active loading and reduce the size of a compressed tablet.
Exemplary United States patents relating to directly compressible tablets include U.S. Pat. No. 3,584,114 to Cavalli, et al., U.S. Pat. No. 3,725,556 to Hanssen, et al., U.S. Pat. No. 3,873,694 to Kanig, U.S. Pat. No. 4,072,535 to Short, and U.S. Pat. No. 4,439,453 to Vogel.
U.S. Pat. No. 5,455,342 discloses starch and other polymers treated with high pressure using a piston apparatus resulting in a starch end-product that manifests several changes in physical properties, including: an altered thermal profile (the onset of melting and the actual melting point is raised, the heat energy required to effect melting is also altered); altered disintegration and solubility properties (the solubility rate in water and other solutions in an ambient or heated environment is slowed by as much as 300%); an altered viscosity profile (pressure treated starch exhibits a higher viscosity for a longer period of time); an altered tableting profile (the treatment of waxy maize pre-gelatinized starches results in a starch which forms harder tablets at lower than conventional compression forces); and an altered turbidity profile (the clarity of solutions made with pressure treated starch is improved).
U.S. Pat. No. 5,455,342 discloses also that pressure treated starch samples are useful as excipients in tableting processes in view of the need for a more readily dissolvable excipient than microcrystalline cellulose. The ""342 patent discloses the direct compression preparation of pharmaceutical tablet compositions including acetaminophen and vitamin C where microcrystalline cellulose (MCC) and untreated starch are replaced with equal amounts of the pressure treated starch. Resulting tablets exhibit acceptable friability, high hardness, and slower dissolution rates than the MCC containing compositions.
U.S. Pat. No. 4,950,484 discloses antibiotic compositions that are wet granulated and compressed and are characterized as including a high percentage of active antibiotic which can be 20-70 wt %, but is preferably 50-65 wt %. These compositions contain a substantial amount of MCC or microfine cellulose in combination with a disintegrant. The ""484 patent disclose also that 20-50 wt %, preferably 35-45 wt % based on the weight of antibiotic of microcrystalline and/or microfine cellulose is used in the granulate, while further amounts, 4-20 wt %, preferably 8-15 wt % based on the weight of the antibiotic, of microcrystalline and/or microfine cellulose are then added to the granulate. These compositions also include 2-20 wt %, preferably 7-10 wt %, based on the weight of the antibiotic of a low-substituted hydroxypropylcellulose as a disintegrant.
U.S. Pat. No. 5,137,730 discloses an improved tablet composition for drugs or active ingredients prone to poor tableting properties. Although the ""730 patent discloses that the premixture used in wet granulation consists essentially of between about 85 and 99.9 percent by weight of the active ingredient and between about 0.1 and 15 percent by weight of citric acid, and one or more other formulation ingredients added to the premixture, the final compressed includes substantially more excipients in the product.
Thus, there still remains a need in the industry for techniques and formulation excipients which would allow artisans to prepare wet granulation and direct compression dosage forms containing relatively high amounts by weight of active ingredient(s) such as for example acetaminophen and vitamin formulations.
Verion Inc. of Lionville, Pa., formerly known as Delta Food Group, Inc. of Aston, Pa., sells the commercially available product, Del Tab(trademark) excipient which is manufactured in accordance with the teachings of U.S. Pat. No. 5,455,342. This product, previously made available under the mark, Delta Starch(copyright), possesses superior properties to microcrystalline cellulose and standard starches used in pharmaceutical and nutritional supplement formulations. The Delta Starch product literature describes that Delta Starch (otherwise identified as DS-901), versions A and C, produce very hard tablets at low compression pressures. For example, a 200 mg tablet made of pure DS-901, pressed at just 1 ton, will possess an average hardness of 20 Kp, and that ideal applications include chewable tablets where mouth feel, tablet strength, yet good friability are required. DS-901-C is described as ideal for direct compression where its performance is comparable to microcrystalline cellulose in most tableting operations. As a wet binder DS-901-C is described as superior to all other conventional pharmaceutical grade starch binders and is also superior to Microcrystalline Cellulose (MCC), requiring less time and less moisture to provide it""s binding function, while also enabling a significant tablet hardness, with friability comparable to Starch 1500 or MCC variations. DS-901-C is described as functioning as an anti-caking agent when used in loading levels from 10 to 35% but also provides a higher tablet hardness than other starches. The product literature describes the following examples of tablets produced with DS 901-C: Formulation VIT-101 used DS-901-C as the diluent and wet binder with Vitamin C. Compared to Starch 1500, DS-901-C used far less moisture and reduced the wet granulation time by half, yet retained tablet hardness, friability and appearance. Formulation VIT-102 used DS-901-C as a direct compression diluent for an extremely hygroscopic compound, choline chloride crystal. DS-901-C provides longer shelf life and greater stability over MCC in this application.
Delta Starch product literature also describes DS901-B as used as a wet binder for pharmaceutical tableting, and is particularly used as a flow control binder for such products as acetaminophen and ascorbic acid formulations which may use from 10 to 35% starch as a binder in fluid bed granulation processing. DS901-B provides excellent binding, while using as much as 30% less water during fluidizing processing, and enabling as much as 50% shorter overall processing times in a wet granulation or fluid bed processing procedure. Additionally the DS 901-B ingredient after wet granulation provides improved compressive strength, higher tablet hardness, and a reduction in the need for critical diluents such as microcrystalline cellulose or lactose, while providing strong tablets with reduced capping and friability. Nonetheless, the product literature does not recognize or suggest that the Delta Starch product could eliminate substantially all of the diluent, binders and hardening agents required in prior art tableting formulations and significantly reduce tablet size while retaining desired tablet properties.
The present invention is based on the surprising discovery that small amounts of polysaccharide tableting excipients previously included in formulations at higher than 10% by weight, including abrupt pressure treated polymeric materials, such as pressure treated starch or dextrin, not only function simply as a binder or hardening agent similar to microcrystalline cellulose, but also possess properties that permit the formulator to eliminate unexpectedly high levels of such excipients in compressible compositions. The present discovery enables the compression manufacture of reduced size tablets and high active loading tablets which otherwise would be difficult and/or expensive to prepare with the standard required amounts of excipients.
The present invention relates to a process for increasing the percentage of active ingredient relative to non-active excipient in a compressible formulation by taking the following steps:
i) determining the formula of a compression formulation including one or more active ingredients and a first amount of one or more non-active hardening or binder excipient or both;
ii) preparing a revised formulation excluding said first amount of excipient and including a polysaccharide material in a second amount of about 50 to about 1 percent by weight of said first amount;
iii) mixing said active ingredients and said polysaccharide material to form a reduced volume mixture; and
iv) compressing the reduced volume mixture to form a high active loaded composition.
The process may be used to form the reduced volume mixture into an object such as a tablet, a pellet, sphere, disk or any shape susceptible to compression formation, such as in tablet stamping or extrusion pelleting. The resulting product is particularly useful as a food, a nutritional supplement or a pharmaceutical composition suitable for animal or human ingestion.
Another aspect of the present invention relates to a process for reducing the size of a first tablet formed by compressing a mixture of active ingredient and an excipient having acceptable hardness and friability and disintegration time, comprising the steps of:
i) mixing said active ingredient with a polysaccharide material, and
ii) compressing the mixture of said ingredient and said polysaccharide material to form a reduced size second tablet,
iii) wherein said excipient consists essentially of one or more hardening agent and binder other than said polysaccharide material, and
iv) wherein said reduced size second tablet excludes about 30 to about 99 percent of said excipient and exhibits an acceptable hardness, friability and disintegration time.
Depending on the compressibility of the active ingredients in the formulation, the ratio of active ingredients to inactive excipients can be increased significantly. Advantages of the present invention include reduced costs of production, improvements in direct compression and wet granulation processing, reduction in patient dosing, reduced tablet size to facilitate dosage acceptability and reduction in choking hazards.
Reduced size tablets produced by the present invention may be manufactured for human or animal consumption and exhibit a hardness and friability within acceptable consumption ranges.